Download pdf - Chemotherapy Induced Nausea Vomiting and Cancer Cachexia … · 2012. 1. 19. · Chemotherapy Induced Nausea Vomiting and Cancer Cachexia Management: Pharmacist Perspectives ... acute

Chemotherapy Induced Nausea Vomiting

and Cancer Cachexia Management:

Pharmacist Perspectives

Suthan Chanthawong B. Pharm, Grad Dip in Pharmacotherapy

Specialized Residency in Internal Medicine

Faculty of Pharmaceutical Sciences, Khon Kaen University

Advanced Pharmacotherapeutics I, 2012

Oncology Section

CINV: Objective

Pathophysiology of chemotherapy induced nausea and vomiting (CINV)

Categories of CINV

Pharmacologic agents indicated for CINV

Current guidelines for CINV

American Society of Clinical Oncology (ASCO)

guideline: 2011 edition

2

Occurs in up to 80% of patients receiving CMT1

In a study of 151 cancer patients from 10 community

oncology centers who were scheduled for their first

cycle of a new CMT regimen, 67% experienced either

acute or delayed CINV during their first CMT cycle.2

Delayed CINV was more common than acute CINV

(59% vs 36%), although many patients experienced

both types

Anticipatory CINV occurs in 18–57%3

1. Nevidjon B, Chaudry R. Supportive Oncology. 2010;8:1-10. 2. Cohen L et al. Support Care Cancer. 2007;15:497-503. 3.

National Comprehensive Cancer Network. Antiemesis. Clinical Practice Guidelines in Oncology. 2010;2.2010.

CINV prevalence

3

Nausea (Subjective quality)

Awareness of the urge to vomit

Retching: Non productive attempt to vomit

Vomiting: Forceful expulsion of GI contents

Intractable nausea

Nausea and vomiting not adequately controlled after multiple antiemetics are used in series and combinations

Anticipatory nausea

Nausea and vomiting occurring as a result of a conditioned response from previous treatment

Definitions of Nausea and Vomiting

4

Medical complications

Electrolyte imbalances

Dehydration

Quality of life

Impact daily functioning

Compliance with chemotherapy

Consequences of CINV

5

Evaluate the most likely etiology of the

patient’s nausea and vomiting

Use pathophysiology knowledge to determine

the likely mechanism and involved receptors

Choose appropriate therapy to target these

receptors

Treatment Approach

6

Acute: Within 24 hours of chemotherapy

Delayed: Occurs > 24 hours after chemotherapy

Anticipatory: Prior to chemotherapy

Breakthrough: While receiving prophylactic antiemetics

Refractory: Not responsive to therapy

Classification of CINV

7

CINV: Classification

Anticipatory Acute Delayed

Chemo

16 - 24 hours 25 - 120 hours

Breakthrough

Refractory/Intractable

8

Common Causes in Cancer Patients

Nausea/ Vomiting

Diseases

Patient

Treatment

9

Age <50 years

Women > men

History of light alcohol use

History of vomiting with prior exposure to chemotherapeutic agents

Other risks

History of motion sickness

History of nausea or vomiting during pregnancy

History of anxiety

Patient-Specific Risk Factors for CINV

ASHP. Am J Health Syst Pharm. 1999:56:729-764; Balfour and Goa. Drugs. 1997:54:273-298. 10

Constipation

Liver metastases

Malignant bowel obstruction

External compression of stomach or intestines by tumor

Primary or metastatic brain

Leptomeningeal disease

Pain medications

Common Causes in Cancer Patients

11

Pathophysiology

Adapted from JAMA 2007;298(10):1196-1207

Chemoreceptor

Trigger Zone Vomiting

Center

Cortex Vestibular System

Peripheral

Pathways

Vagus and

splanchnic

nerves

Intracerebral

projections Vestibular nuclei

projections

Mechanical stretch

GI mucosal injury

Local toxins

Drugs

Metabolic products

Bacterial toxins

Motion

Labyrinth disorders

Sensory input

Anxiety

Increased ICP

D2 5HT3

NK1

5HT3

Chemo-

receptors

ACh

H1

ACh

H1

5HT3

12

Neurotransmitter Involvement

13

5-HT3

Other factors

Acute

Delayed

Chemotherapy-Induced Emesis:

Key Treatment Milestones

Palonosetron July, 2003 Aprepitant, March 2003

14

Serotonin Antagonists

Corticosteroids

NK1 Receptor Antagonist (i.e. Aprepitant)

Dopamine antagonists

Metoclopramide

Phenothiazines (i.e. Prochloroperazine)

Butyrophenones (i.e. Haloperidol)

Benzodiazepines

Cannabinoids (i.e. Marinol®)

Classes of Antiemetic Agents

15

ASCO Guideline

Current guidelines for CINV

American Society of Clinical Oncology (ASCO)

guideline: 2011 edition

16

Guideline Methodology: Systematic Review

A systematic review provided preliminary literature for consideration:

Agency for Healthcare Research and Quality (AHRQ)-

funded Oregon Evidence-Based Practice Center

An ASCO Update Committee considered pertinent literature through

February 2010:

MEDLINE

Cochrane Collaboration Library

ASCO Annual Meetings

Multinational Association for Supportive Care in

Cancer (MASCC) Meetings

17

Categories for Antiemetics in Oncology

Chemotherapy-Induced Nausea and Vomiting

(CINV)

Emetic risk of chemotherapy

Combination chemotherapy

Anticipatory nausea and vomiting

Complementary therapy

Adjunctive therapy

Anticipatory CINV

18

Categories for Antiemetics in Oncology

CINV (cont’d)

Special populations

High Dose Chemotherapy

Multi-day chemotherapy

Pediatric Populations

Radiation-Induced Nausea and Vomiting (RINV)

Emetic risk by radiation site

Combined chemotherapy and radiation therapy

19

CHEMOTHERAPY-INDUCED

NAUSEA AND VOMITING

20

Emetic Risk Categories*

Four emetic risk categories:

High (>90%)

Moderate (30%-90%)

Low (10%-30%)

Minimal (<10%)

*Antiemetic risk categories were developed from historic studies

21

2011 Emetic Risk Categories of

Single Agents Antineoplastics

Emetic Risk Antineoplastic Agents Administered Intravenously

High Moderate Low Minimal

Carmustine

Cisplatin

Cyclophosphamide

>1500 mg/m2

Dacarbazine

Dactinomycin

Mechlorethamine

Streptozotocin

Azacitidine

Alemtuzumab

Bendamustine

Carboplatin

Clofarabine

Cyclophosphamide

<1500 mg/m2

Cytarabine >1000

mg/m2

Daunorubicin*

Doxorubicin*

Epirubicin*

Idarubicin*

Ifosfamide

Irinotecan

Oxaliplatin

Fluorouracil

Bortezomib

Cabazitaxel

Catumaxomab

Cytarabine

<1000 mg/m2

Docetaxel

Doxorubicin HCL

liposome injection

Etoposide

Gemcitabine

Ixabepilone

Methotrexate

Mitomycin

Mitoxantrone

Paclitaxel

Panitumumab

Pemetrexed

Temsirolimus

Topotecan

Trastuzumab

2-Chlorodeoxyadenosine

Bevacizumab

Bleomycin

Busulfan

Cetuximab

Fludarabine

Pralatrexate

Rituximab

Vinblastine

Vincristine

Vinorelbine

*These anthracyclines, when combined with cyclophosphamide, are now designated as high emetic risk 22

Recommendation by Risk Category, HEC

2011 Recommendation:

Three drug combination of

NK1 antagonist,

5-HT3 receptor antagonist, and

Dexamethasone

Adriamycin and Cyclophosphamide combination

regimens re-classified as HEC

23


2011 Recommendation: Dosing

Day 1:

NK1 antagonist (aprepitant 125 mg OR fosaprepitant 150 mg)

5-HT3 receptor antagonist (options on next slide)

Dexamethasone 12 mg

Day 2:

Dexamethasone 8 mg + if NK1 antagonist = aprepitant, then aprepitant 80 mg

Day 3:

Dexamethasone 8 mg (dexamethasone may be given for 3 or 4 days) + if NK1

antagonist = aprepitant, then aprepitant 80 mg

24


5-HT3 Receptor Antagonist Dosing

5-HT3 Receptor

Antagonist Intravenous Oral

Granisetron 1 mg or 0.01 mg/Kg 2 mg

Ondansetron 8 mg or 0.15 mg/Kg 8 mg twice daily

Palonosetron 0.25 mg 0.50 mg

Dolasetron 100 mg IV formulation NOT

recommended

Ramosetron 0.3 mg ---

Tropisetron 5 mg 5 mg

25

Olanzapine: HEC

A pilot study, compared olanzapine with aprepitant,

both in combination with palonosetron and

dexamethasone.

Patients randomly assigned to olanzapine

experienced CR rates similar to those of patients

who received aprepitant.

The olanzapine arm was superior for nausea control

during the overall study period (P.01).

Additional trials are necessary to define the role of

olanzapine in this setting.

26

Navari R, et al. 2010 MASCC, June 24-26, 2010 (abstr 02-010)

Recommendation by Risk Category, MEC


Two drug combination of palonosetron and dexamethasone

If palonosetron is not available, any of the first-generation 5-HT3

receptor antagonists may be used- preferably ondansetron or

granisetron

Dosing:

Palonosetron 0.25 g IV OR 0.50 mg oral, day 1 only

Dexamethasone 8 mg (IV or oral), days 1-3

27

Recommendation by Risk Category, MEC

Aprepitant* not recommended, though clinicians

may consider its use

If clinicians opt to use aprepitant, dosing:

Aprepitant: 125 mg day 1, 80 mg days 2 and 3

5-HT3 receptor antagonist dosing as previous slide,

no preferred agent

Dexamethasone: 12 mg on day 1 ONLY

*Note: No data available at the time of the update on

fosaprepitant in moderate risk setting

28

Recommendation by Risk Category, LEC


Low Emetic Risk:

A single 8 mg dose of dexamethasone before

chemotherapy is suggested.

Minimal Emetic Risk:

No antiemetic should be administered routinely

before or after chemotherapy.

29

CINV: Combination Chemotherapy


Administer antiemetics appropriate for the

component chemotherapeutic agent of greatest

emetic risk

Note: adriamycin and cyclophosphamide

combinations are now classified as HEC

30

CINV: Adjunctive Drugs

2011 Recommendation: Lorazepam and diphenhydramine are useful

adjuncts to antiemetic drugs, but are not recommended as

single agent antiemetics

Olanzapine combination with NK1 antagonist plus

dexamethasone

31

CINV: Complementary therapy

2011 Recommendation: No published RCT data which met inclusion criteria

(for the systematic review) are currently available to

support a recommendation about such therapies

32

Special Emetic Populations: High-Dose

Chemotherapy with SCT or BMT


A 5-HT3 receptor antagonist combined with

dexamethasone is recommended.

Aprepitant should be considered, although

evidence to support its use is limited.

33

Special Emetic Populations:

Multi-day Chemotherapy


Antiemetics appropriate for the emetogenic risk

class of the chemotherapy should be administered

for each day of the chemotherapy and 2 days

afterward, if appropriate

Based on limited data, patients receiving 5-day

cisplatin regimens should receive

aprepitant + 5-HT3 receptor antagonist + dexamethasone

Special Emetic Populations: Vomiting and

Nausea Despite Recommended Prophylaxis

2011 Recommendation Re-evaluate emetic risk, disease status, concurrent

illness, and medications;

Ascertain that the best regimen is being given for the

emetic risk;

Consider adding lorazepam or alprazolam to the

regimen; and,

Add olanzapine or substitute high-dose

intravenous metoclopramide instead of 5-HT3 receptor

antagonist or add dopamine antagonist.

35

Special Emetic Populations: Anticipatory Emesis

Anticipatory Emesis:

Begins before treatment

May occur in patients with poor control of vomiting during prior

chemotherapy


Clinicians should always use the antiemetic regimen

recommended for the initial chemotherapy based on emetic risk

Use the most active antiemetic regimens appropriate for

chemotherapy

Behavioral therapy with systematic desensitization

36

Special Emetic Populations:

Pediatric Oncology Patients

Few research trials evaluate antiemetic therapy in children

receiving cancer therapy

2011 Recommendations:

A 5-HT3 receptor antagonist plus a corticosteroid is suggested before chemotherapy in children receiving chemotherapy of HEC or MEC.

Due to variation of pharmacokinetic parameters in children, higher weight-based doses of 5-HT3 receptor antagonists than those used in adults may be required.

37

RADIATION-INDUCED

INDUCED NAUSEA AND

VOMITING (RINV)

38

RINV: Emetic Risk Categories of Radiation

Emetic Risk Irradiated area

High Total Body (TBI)

Total Nodal Irradiation

Moderate

Upper Abdomen

Upper Body Irradiation

Half Body Irradiation

Low Lower Thorax and Pelvis

Cranium, Craniospinal, and Head & Neck

Minimal Extremities

Breast

39

RINV: 5-HT3 Receptor Antagonist Dosing

5-HT3 Receptor Antagonist Dosing

5-HT3 Antagonist Intravenous Oral

Granisetron1

(preferred) 1 mg or 0.01 mg/Kg 2 mg

Ondansetron1

(preferred) 8 mg or 0.15 mg/Kg 8 mg twice daily

Palonosetron2 0.25 mg 0.50 mg

Dolasetron 100 mg IV formulation NOT

recommended

Tropisetron 5 mg 5 mg

1 Preferred agents, 2 No data on dosing frequency available, every 2nd or 3rd day suggested

40

RINV: Moderate Emetic Risk

2011 Recommendation

5-HT3 receptor antagonist, before each fraction and at

least 24 hours after end of XRT, and a 5-day course of

dexamethasone during fractions 1-5.

Dosing: 5-HT3 receptor antagonist as previous slides

Dexamethasone: 4mg oral or IV, fractions 1-5

41

RINV: Moderate Emetic Risk

2011 Recommendation

5-HT3 receptor antagonist before each fraction,

throughout course of radiotherapy.

Patients may be offered a short course of

dexamethasone during fractions 1-5.

Dosing:

5-HT3 receptor antagonist: as previous slides

Consider- Dexamethasone: 4mg oral or IV,

fractions 1-5

42

RINV: Low Emetic Risk

2011 Recommendation

5-HT3 receptor antagonist* as rescue or prophylaxis

For patients who experience RINV while receiving

rescue therapy only, prophylactic treatment should

continue until radiotherapy is complete.

Dosing:

5-HT3 receptor antagonist: as previous slides

43

RINV: Minimal Emetic Risk

2011 Recommendation

5-HT3 receptor antagonist* as rescue or prophylaxis

Prophylactic antiemetics should continue throughout

radiation treatment if a patient experiences RINV while

receiving rescue therapy.

Dosing:

5-HT3 receptor antagonist: see slide 26

Dopamine receptor antagonist: metoclopramide 20 mg

oral or prochlorperazine 10 mg oral or IV

44

Nausea and vomiting during concurrent

radiation therapy and chemotherapy

Determine antiemetic therapy according to the

emetic risk of the chemotherapy, unless emetic risk

with planned radiotherapy is higher.

45

New Antiemetics:

FDA approvals since 2006 update

Fosaprepitant

NK1 antagonist, intravenous aprepitant pro-drug

Acceptable where NK1 antagonist indicated

Granisetron transdermal system

Patch delivers granisetron continuously over five days

Option for multi-day chemotherapy and high or moderate risk

radiation therapy

Ondansetron ODT

Orally disintegrating tablet

Acceptable where 5-HT3 receptor antagonist indicated

46

2011Update Recommendation Changes

CINV

Highly emetogenic agents: A/C combinations re-classified as highly emetic

Moderately emetogenic agents: Palonosetron preferred 5-HT3 receptor antagonist

Low emetogenic agents No change

Minimally emetogenic agents No change

Combination chemotherapy No change

Adjunctive drugs No change

Complementary Therapy New question for 2011

2011Update Recommendation Changes, cont’d

CINV, cont’d

Pediatric Patients No change

High-dose chemotherapy with SCT or BMT Consider the addition of aprepitant to antiemetic regimen

Multi-day chemotherapy Recommended antiemetic regimen for patients receiving 5-day cisplatin:

aprepitant + 5-HT3 receptor antagonist + dexamethasone

Emesis or Nausea despite optimal prophylaxis Option of adding olanzapine to antiemetic regimen

Anticipatory nausea and vomiting No change

48

RINV

• High Risk RINV – Addition of 5-day course of dexamethasone during fractions 1-5

• Moderate Risk – Consider offering 5-day course of dexamethasone during fractions 1-5

• Low risk – 5-HT3 receptor antagonist as either prophylaxis or rescue

– Patients requiring rescue should receive subsequent prophylactic antiemetic

therapy

• Minimal risk – Patients requiring rescue should receive subsequent prophylactic antiemetic

therapy

• Combined chemotherapy and radiation therapy – No change

49

2011Update Recommendation Changes, cont’d

Chemotherapy Induced Nausea Vomiting

and Cancer Cachexia Management:

Pharmacist Perspectives

Suthan Chanthawong B. Pharm, Grad Dip in Pharmacotherapy

Specialized Residency in Internal Medicine

Faculty of Pharmaceutical Sciences, Khon Kaen University

Advanced Pharmacotherapeutics I, 2012

Oncology Section

Objective

Identify treatment-related nutrition deficiencies in cancer patients and management strategies

Outline the application and limitations of the A.S.P.E.N. Guidelines in the care of patients with cancer

Describe the clinical dilemmas presented with utilizing nutritional support in the various stages of cancer progression

51

Checking Point

All cancer patients are nutritionally-at-risk. A. True

B. False

Nutrition support therapy has been shown to

significantly impact quality of life and mortality in

oncology patients. A. True

B. False

What is cancer cachexia?

An extreme on the continuum of wt loss in

cancer

Due to systemic inflammatory response

Mediate through PIF and LMF

Frequency of weight loss in cancer cachexia?

Dewys, et al. Amer J Med. 1980;69:491-497.

Aetiology of Cancer Cachexia

Alterations of metabolic pathways

Malnutrition

Metabolic competition: Tumor vs Host

Clinical consequences of cancer cachexia

Host-tumour

interaction

Metabolic

dysregulation

Clinical

endpoints

Tumour factors Proinflammatory

Pro-cachectic

Host response Acute phase protein response

Neuroendocrine dysregulation

Host-tumour interaction Systemic inflammation

Protein metabolism

Proteolysis

Lipid metabolism

Lipolysis

Increased resting energy

expenditure (REE)

Weight loss

Decreased lean body

mass and fat deposits

Anorexia

Reduced overall survival

Decreased quality of life

Reduced physical activity

Donohoe CL, et al. Gastroenterology Research and Practice 2011:

doi:10.1155/2011/601434

57

Nutrition Impact on Cancer Treatment

Intervention Type Effects

Surgery Oropharyngeal Difficult swallow, tube feeding dependent

Esophagous Gastric stasis, regurgitation, early satiety

Stomach Malabsorption, early satiety, hypoglycemia

Colon Water loss, electrolyte loss

Radiation Acute Diarrhea, bleeding, N/V, mucositis, xerostomia

Chronic Stricture, fibrosis, dysphagia, malabsorption

CMT Cytotoxic Anorexia, NV, mucositis, enteritis, Electrolyte

imbalance, oragan dysfunction

Immunotherapy Anorexia, fluid retention, N/V, diarrhea

Steroids Fluid/electrolyte imbalances, hyperglycemia

Daly JM, et al. In: ACS Textbook of Clinical Oncology. 1995:580-596.

Roberts S, et al. In: The A.S.P.E.N. Nutrition Support Core Curriculum. 2007:649-675.

Clinical Features

Hypophagia / anorexia

Early satiety

Anaemia

Wt loss with depletion

Alteration of body compartments

Oedema

Asthenia (weakness)

Diagnosis of Cancer Cachexia

Weight loss or BMI <20 kg/m2

Mild ≥ 5% in 1 mo.

Mod ≥ 7.5 % in 3 mo.

Severe ≥ 10% in 6 mo.

And 3/5

from:

Decreased muscle strength

Fatigue

Anorexia

Low fat-free mass index

Abnormal biochemistry:

Increased inflammatory markers (CRP, IL-6)

Anaemia (Hb < 12 g/dL)

Low serum albumin (<3.2 g/dL)

Note:

• Fatigue is defined as physical and or mental weariness resulting from exertion; an inability to continue exercise at the same intensity with

a resultant deterioration in performance.

Anorexia is defined as limited food intake (total caloric intake less than 20 kcal/kg body weight/day) or poor appetite.

Low-fat-free mass index represents lean tissue depletion (i.e., mid upper arm muscle circumference <10th percentile for age and gender’

appendicle skeletal muscle index by DEXA <5.45 (kg/m2) in females and <7.25 in males).

Evan WJ, et al. Clinical Nutrition 2008;27(6):793–799.

Cancer Cachexia Management

Identify treatment-related nutrition impact

Prophylactic pharmacotherapy

Nausea, vomiting, xerostomia, pain, etc.

Need for nutrition support therapy?

Severe malnutrition

Anticipated prolonged NPO

Difficulty swallowing

Counseling by nutrition support specialist

Dietician, pharmacist, physician

Goal of Nutrition Support

Improve the subjective quality of life (QoL)

Enhance anti-tumour treatment effects

Reduce the adverse effects of anti-tumour

therapies

Prevent & treat undernutrition

Arends et al., 2006

Resting Energy Expenditure

In cancer patients, REE can be: Unchanged

Increased

Decreased

Many cancer patients are mildly hypermetabolic with

an excess energy expenditure of between 138-289

kcals per day

If not compensated by ↑ energy intake results in loss

of 1.1 - 2.3 kg muscle mass & 0.5 – 1.0 kg body fat /

month

Hyltander et al., 1991, Bozzetti F et al.,1980

Energy Requirement

For non obese cancer patients total energy

expenditure is approx:

30-35kcal/kgBW/d in ambulant patients

20-25kcal/kgBW/d in bedridden patients

Assumptions are less accurate for underweight individuals

(TEE per kg is higher in this group)

Published reference calculations are more accurate for

underweight cancer patients

Arends et al., 2006, Harris & Benedict 1919, Schofield 1985

Vitamin and Mineral Requirement

Vitamins & Minerals Lack of evidence surrounding requirements in

oncological disease

For EN recommendations are based on RDA’s

Inclusion of increased doses of anti-oxidant

vitamins could be considered but at present

lack data to demonstrate clinical benefit

PEN Group, 2004, ASPEN, 2002, Arends et al., 2006

Pharmacologic Agent for Cancer Cachexia

Megestrol acetate 160-1600 mg PO OD

Medroxyprogesterone 300-1000 mg PO OD

Dronabinol 2.5 mg PO BID

Dexamethasone 0.75 mg PO QID

Prednisolone 10 mg PO BID

Endpoints for evaluating interventions

Clinical Functional Biochemical

Nutritional

status

Performance score

(ECOG; Karnofsky)

Plasma fatty acid

composition

Tolerance of diet Quality of life scores Pro-inflammatory

cytokines

GI symptoms Appetite Acute phase protein

reactants

Infections Fatigue

Survival Physical activity as

measured electronically

Muscle strength

Mantovani G, et al. Nutrition 2008;24(4):305–313.

Summary

Cancer is increasingly becoming a chronic / “long

term” condition

Early identify nutrition status

Counselling by nutrition support specialist

Prophylactic management and control of adverse event

Long term follow-up and assessment of therapy

related complications

Regular reassessment is vital in order to maximise the

therapeutic potential of nutritional support